The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).

Bernard-Soulier syndrome with severe bleeding: absent platelet glycoprotein Ib alpha due to a homozygous one-base deletion.

Bernard-Soulier syndrome is a rare congenital platelet disorder that affects a surface membrane adhesion receptor, glycoprotein (GP) Ib-V-IX. Both the genetic defects and the bleeding diatheses associated with the syndrome are heterogeneous due, in part, to the complexity of the involved receptor which consists of four different members, GPs: Ib alpha-Mr 143 K (contains the von Willebrand factor-binding site), Ib beta-Mr 22 K, V-Mr 83 K and IX-Mr 20 K. We studied a kindred that includes a 40 year-old man with severe Bernard-Soulier syndrome: life-threatening gastrointestinal bleeding, thrombocytopenia, giant platelets and absent ristocetin-dependent platelet aggregation. By Southern blotting, PCR amplification/sequencing, hetero-duplex analysis, and allele-specific oligonucleotide hybridization, the Ib-V-IX genes were analyzed, and the molecular genetic defect was defined as a one-base deletion in the GPIb alpha gene, involving an adenine of codon 19. The mutation, K19R, homozygous in the propositus and heterozygous in the available unaffected relatives, leads to a frame shift in codons 19-21 and a premature stop codon after codon 21. No functional GPIb alpha can be produced from the mutant allele, implying that the platelets of the affected patient lack all GPIb alpha. Within the spectrum of Bernard-Soulier syndrome, this patient's disorder exemplifies a severe or "classic" extreme; an "experiment of Nature" that illustrates the effect of a complete deficiency of the ligand-binding chain (GPIb alpha) of the GPIb-V-IX receptor.

Phase II study of pulse 5-fluoro-2'-deoxyuridine and leucovorin in advanced colorectal cancer patients previously treated with chemotherapy.

Because of possibly better activity against colorectal cancer of 5-fluoro-2'-deoxyuridine [floxuridine (FUdR)] compared to 5-fluorouracil (5-FU), and because of improved therapeutic results of leucovorin (LV) modulation of 5-FU, we carried out a phase II study of systemic FUdR and LV in 5-FU-treated patients with metastatic colorectal cancer. Weekly regimens consisted of a 4-hour infusion of LV, 200 mg/m2, and at 2 hours, a 2-hour infusion of FUdR, 30 mg/kg, with weekly dose escalation, as tolerated, to a maximum of 60 mg/kg. Twenty-nine patients were treated; they had a median age of 66, most had good performance status, and all had measurable disease. All had received 5-FU, although three had received it as adjuvant therapy only. Two patients had partial responses (6.9% response rate, 95% confidence interval, 1.9-21.9%) lasting 29 and 19 weeks, and five had stable disease. Median time to progression was 8 weeks and median survival was 36.5 weeks. The median number of courses was 6.5; escalation of FUdR was carried out in 27 patients. Hematologic toxicity was minimal and gastrointestinal toxicity was most frequent, although mild. This regimen, although well tolerated, is minimally effective in previously 5-FU-treated patients with metastatic colorectal cancer.

Paroxysmal nocturnal hemoglobinuria terminating as erythroleukemia.

A case of a patient who developed erythroleukemia 3 years into the course of paroxysmal nocturnal hemoglobinuria (PNH) is presented. A case of erythroleukemia with a positive sucrose lysis test has been reported, but our case appears to be the first with a long clinical course of PNH evolving into erythroleukemia. The association between these two diseases, their possible clonal origin, and how they fit into the myelodysplastic syndromes are discussed.

Cimetidine and hematologic suppression: things are not always as they appear.

A 67-year-old man with a bleeding ulcer developed fever, thrombocytopenia, and neutropenia with eosinophilia coincidental to receiving 3600 mg of cimetidine. Failure to reduplicate the hematologic suppression after cimetidine rechallenge suggests the drug was not responsible for the change in circulating cells. Our patient is similar to the earlier reported cases of cimetidine-associated hematologic suppression. The role of cimetidine in these cases is impossible to determine because of the multifactorial possibilities for bone-marrow suppression. Recently, a fatal case of agranulocytosis associated with cimetidine has been reported. The possible mechanisms of granulocytopenia are reviewed, and it is suggested cimetidine may cause bone-marrow suppression by an idiosyncratic reaction. We believe the possibility of fatal aplastic anemia secondary to cimetidine is very rare and does not preclude a drug rechallenge when the benefit-risk ration warrants.

Porcine factor VIII and plasmapheresis in the management of hemophiliac patients with inhibitors.

Management of hemophiliac patients with inhibitors can be a difficult problem. We report here a patient with severe hemophilia A, a high titer inhibitor, and an abdominal abscess requiring surgery. Despite significant cross reactivity of the inhibitor with porcine FVIII, he was successfully managed with plasmapheresis and porcine FVIII infusions. Other approaches to the management of such patients are briefly reviewed.

Pulmonary blastoma. Case report and literature review of chemotherapy experience.

Pulmonary blastoma is a rare primary lung neoplasm, occurring in both children and adults, which is pathologically, clinically, and prognostically distinct from other lung tumors. Usually it has been treated with surgery, but both chemotherapy and radiotherapy have been used for metastatic disease, and in the adjuvant setting. A patient is described who presented with metastatic pulmonary blastoma. Treatment with cyclophosphamide, vincristine, doxorubicin, and dactinomycin resulted in an objective response as judged by standard criteria. The literature is reviewed for other experience with chemotherapy in this rare lung tumor. This four-drug combination appears to show promise for tumor response, and is deserving of further trial.